The main goal of this research program is to identify novel druggable pathways to combat castration-resistant prostate cancer (CRPC), the therapy-resistant, lethal form of prostate cancer. The principal approach is to rigorously scrutinize novel biochemical pathways the lab has implicated in CRPC using a genetic loss-of-function screen, which enabled the upfront discovery of alterations that cause therapy (i.e. castration) resistance. In addition to known tumor suppressive pathways - SRC inhibitory kinase CSK and GSK3, which were further validated in tissue culture studies, animal models, and human prostate cancer tissue samples, the screen implicated several additional pathways, namely those impinging on NF-?B and the eukaryotic translation initiation factor 2? (eIF2?). In the present exploratory R21 project, one of these newly implicated pathways will be dissected in two specific aims: (i.) In tissue culture models, the contributions of deficiency in eIF2? phosphorylation to androgen deprivation-induced growth arrest will be determined. (ii.) The functional role of these pathways will be examined in mouse models (xenografts, transgenics). Not only will these new target pathways be validated functionally, but their activity will also be modified with existing drug-like compounds in order to provide proof-of-concept that they are amenable to pharmacotherapy (i.e. druggable). Notably, this approach has met with great success in the previous studies on SRC/CSK. Within two years, the planned investigations are expected to provide a strong rationale for either advancing an existing drug-like compound into clinical development/application or for initiating a screen for small molecules able to modulate the pathways these studies will causally implicate in the therapy resistance of CRPC.